Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models

Abstract

IntroductionModulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats.MethodsAnimals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS.ResultsIn wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF.ConclusionsTaken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.

γ-Secretase inhibitors and modulators

“…This has led to the identification of a number of acidic GMSs with dramatic increases in potency and brain penetrance, and non-acidic GSMs based around a common scaffold that are also much more potent than the first generation NSAID-based GSMs (Figure 3) [155-172]. More recently triterpenoid natural product derived GSMs have been identified [173-174]. Overall there are subtle differences between these GSMs that may be therapeutically important.…”

“…While the more potent acidic GSMs show the classic GSM signature of lowering Aβ1-42 and increasing Aβ1-38 [175], nonacidic GSMs increase Aβ1-37 and 1-38 and lower both Aβ1-40 and 1-42 [171]. In contrast, the triterpenoid GSM appears to be even more distinct lowering both Aβ1-38 and 1-42 [173-174]. These differential properties and comparison to GSIs are described in Table 2.…”

“…Although not directly established non-acidic GSMs appear would be proposed to increase processivity of Aβ1-40 and Aβ1-42 to Aβ1-37 and Aβ1-38. The novel triterpenoid GSMs recently described by Satori Pharmaceuticals, are somewhat unusual as they decrease both Aβ1-38 and Aβ1-42 [173-174]. How this unusual type of modulation occurs is unclear, but could be accounted for either by effect on the substrate product line that is determined by the initial γ-secretase cleavage (i.e.…”

γ-Secretase Modulators

“…In vivo profiling of (74) revealed that the acetate group was rapidly hydrolysed, in addition to the much slower hydrolysis of the tri-hydroxy THP. Further optimisation resulted in the identification of SPI-1865 (79) [74] ( Figure 3.17) (full structure not disclosed) which was selected as a development compound. In a mouse PK study, compound (75) displayed a moderate clearance of 3.1 L/h/kg, a high distribution volume of 12.1 L/kg, a long half-life of 6.5 h and moderate oral bioavailability at 37%, in addition to good CNS penetration with a Br:Pl ratio of 1.7 at the 6 h time point.…”

Minimization of drug–drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators

“…Based on these results combined with the efficacy and CYP inhibition data, compound 14 was chosen as a candidate for preclinical development. 10 We found that our initial lead compounds were likely DDI perpetrators due to their potent CYP3A4 inhibition. Structure-activity relationships aided by in silico modeling of these compounds revealed options for avoiding these liabilities.…”